chr4-3463421-G-T

Variant names:

• chr4-3463421-G-T
• rs764824461
• NM_173660.5:c.46G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_173660.5(DOK7):​c.46G>T​(p.Gly16Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000459 in 1,306,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000046 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain PH (size 105) in uniprot entity DOK7_HUMAN there are 13 pathogenic changes around while only 3 benign (81%) in NM_173660.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.46G>T	p.Gly16Cys	missense_variant	Exon 1 of 7	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.46G>T	p.Gly16Cys	missense_variant	Exon 1 of 7	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000112 AC: 1 AN: 89144 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 50858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000830

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000459 AC: 6 AN: 1306786 Hom.: 0 Cov.: 49 AF XY: 0.00000310 AC XY: 2 AN XY: 645582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000429

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000479

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.46G>T (p.G16C) alteration is located in exon 1 (coding exon 1) of the DOK7 gene. This alteration results from a G to T substitution at nucleotide position 46, causing the glycine (G) at amino acid position 16 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	0.0086	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.011	D;D;.
Polyphen		1.0	.;D;.
Vest4		0.49
MutPred		0.44		Gain of glycosylation at S21 (P = 0.0131);Gain of glycosylation at S21 (P = 0.0131);Gain of glycosylation at S21 (P = 0.0131);
MVP		0.90
MPC		0.018
ClinPred		0.98	D
GERP RS		2.3
Varity_R		0.66
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs764824461; hg19: chr4-3465148;